The present invention is concerned with novel aniline derivatives, their manufacture and their use as medicaments. The compounds of the present invention inhibit 2,3-oxidosqualene-lanosterol cyclase (EC5.4.99.) which is required for the biosynthesis of cholesterol, ergosterol and other sterols.
Causal risk factors that directly promote the development of coronary and peripheral atherosclerosis include elevated low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), hypertension, cigarette smoking and diabetes mellitus. Other synergistic risk factors include elevated concentrations of triglyceride (TG)-rich lipoproteins, small, dense low-density lipoprotein particles, lipoprotein (a) (Lp(a)), and homocysteine. Predisposing risk factors modify the causal or conditional risk factors and thus affect atherogenesis indirectly. The predisposing risk factors are obesity, physical inactivity, family history of premature CVD, and male sex. The strong connection between coronary heart disease (CHD) and high LDL-C levels in plasma, and the therapeutic advantage of lowering elevated LDL-C levels are now well established (Gotto et al., Circulation 81, 1990, 1721-1733; Stein et al., Nutr. Metab. Cardiovasc. Dis. 2, 1992, 113-156; Illingworth, Med. Clin. North. Am. 84, 2000, 23-42). Cholesterol-rich, sometimes unstable, atherosclerotic plaques lead to the occlusion of blood vessels resulting in an ischemia or an infarct. Studies with respect to primary prophylaxis have shown that a lowering of plasma LDL-C levels in plasma reduces the frequency of non-fatal incidences of CHD, while the overall morbidity remains unchanged. The lowering of plasma LDL-C levels in patients with pre-established CHD (secondary intervention) reduces CHD mortality and morbidity; meta-analysis of different studies shows that this decrease is proportional to the reduction of the LDL-C (Ross et al., Arch. Intern. Med. 159, 1999, 1793-1802).
The clinical advantage of cholesterol lowering is greater for patients with pre-established CHD than for asymptomatic persons with hypercholesterolemia. According to current guidelines, cholesterol lowering treatment is recommended for patients who had survived a myocardial infarct or patients suffering from angina pectoris or another atherosclerotic disease, with a target LDL-C level of 100 mg/dl.
Preparations such as bile acid sequestrants, fibrates, nicotinic acid, probucol as well as statins, i.e. HMG-Co-A reductase inhibitors such as simvastatin and atorvastatin, are used for usual standard therapies. The best statins reduce plasma LDL-C effectively by at least 40%, and also plasma triglycerides, a synergistic risk factor, but less effectively. In contrast, fibrates reduce plasma triglycerides effectively, but not LDL-C. Combination of a statin and a fibrate proved to be very efficacious in lowering LDL-C and triglycerides (Ellen and McPherson, J. Cardiol. 81, 1998, 60B-65B), but safety of such a combination remains an issue (Shepherd, Eur. Heart J. 16, 1995, 5-13). A single drug with a mixed profile combining effective lowering of both LDL-C and triglycerides would provide additional clinical benefit to asymptomatic and symptomatic patients.
In humans, statins are well tolerated at standard dosage, but reductions in non-sterol intermediates in the cholesterol synthesis pathway, such as isoprenoids and coenzyme Q, may be associated with adverse clinical events at high doses (Davignon et al., Can. J. Cardiol. 8, 1992, 843-864; Pederson and Tobert, Drug Safety 14, 1996, 11-24).
This has stimulated the search for, and development of compounds that inhibit cholesterol biosynthesis, yet act distal to the synthesis of these important, non-sterol intermediates. 2,3-oxidosqualene:lanosterol cyclase (OSC), a microsomal enzyme, represents a unique target for a cholesterol-lowering drug (Morand et al., J. Lipid Res., 38, 1997, 373-390; Mark et al., J. Lipid Res. 37, 1996, 148-158). OSC is downstream of farnesyl-pyrophosphate, beyond the synthesis of isoprenoids and coenzyme Q. In hamsters, pharmacologically active doses of an OSC inhibitor showed no adverse side-effects, in contrast to a statin which reduced food-intake and body weight, and increased plasma bilirubin, liver weight and liver triglyceride content (Morand et al., J. Lipid Res., 38, 1997, 373-390). The compounds described in European Patent Application No. 636 367, which inhibit OSC and which lower the total cholesterol in plasma, belong to these substances.
OSC inhibition does not trigger the overexpression of HMGR because of an indirect, negative feed-back regulatory mechanism involving the production of 24(S),25-epoxycholesterol (Peffley et al., Biochem. Pharmacol. 56, 1998, 439-449; Nelson et al., J. Biol. Chem. 256, 1981, 1067-1068; Spencer et al., J. Biol. Chem. 260, 1985, 13391-13394; Panini et al., J. Lipid Res. 27, 1986, 1190-1204; Ness et al., Arch. Biochem. Biophys. 308, 1994, 420-425). This negative feed-back regulatory mechanism is fundamental to the concept of OSC inhibition because (i) it potentiates synergistically the primary inhibitory effect with an indirect down-regulation of HMGR, and (ii) it prevents the massive accumulation of the precursor monooxidosqualene in the liver. In addition, 24(S),25-epoxycholesterol was found to be one of the most potent agonists of the nuclear receptor LXR (Janowski et al., Proc. Natl. Acad. Sci. USA, 96, 1999, 266-271). Considering that 24(S),25-epoxycholesterol is a by-product of inhibition of OSC it is hypothesized that the OSC inhibitors of the present invention could also indirectly activate LXR-dependent pathways such as (i) cholesterol-7alpha-hydroxylase to increase the consumption of cholesterol via the bile acid route, (ii) expression of ABC proteins with the potential to stimulate reverse cholesterol transport and increase plasma HDL-C levels (Venkateswaran et al., J. Biol. Chem. 275, 2000, 14700-14707; Costet et al., J. Biol. Chem. June 2000, in press; Ordovas, Nutr Rev 58, 2000, 76-79, Schmitz and Kaminsky, Front Biosci 6, 2001, D505-D514), and/or inhibit intestinal cholesterol absorption (Mangelsdorf, XIIth International Symposium on Atherosclerosis, Stockholm, June 2000). In addition, possible cross talks between fatty acid and cholesterol metabolism mediated by liver LXR have been hypothesized (Tobin et al., Mol. Endocrinol. 14,2000, 741-752).
The invention relates to a compound of the formula (I) 
wherein
U is O or a lone pair,
Y is C or N,
V is O, S, NR6, xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94, if Y is C, or xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, if Y is N,
W is CO, COO, CONR1, CSO, CSNR1, SO2, or SO2NR1,
L is lower-alkylene, lower-alkenylene, or a single bond,
A1 is H, lower-alkyl, or lower-alkenyl,
A2 is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl, or lower-alkinyl, each unsubstituted or substituted by R2,
A3, A4 are hydrogen or lower-alkyl, or
A1 and A2 or A1 and A3 are bonded to each other to form a ring and xe2x80x94A1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94A3xe2x80x94 are lower-alkylene or lower-alkenylene, each unsubstitued or substituted by R2, or are lower-alkylene or lower-alkenylene, each unsubstitued or substituted by R2, in which one xe2x80x94CH2xe2x80x94 group of xe2x80x94A1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94A3xe2x80x94 is replaced by NR3, S, or O,
A5 is lower-alkyl,
X is hydrogen or one or more halogen substituents,
A6 is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, heterocycloalkyl-lower-alkyl, lower alkenyl, lower-alkadienyl, aryl, aryl-lower-alkyl, heteroaryl, or heteroaryl-lower-alkyl,
R2 is hydroxy, hydroxy-lower-alkyl, lower-alkoxy, N(R4,R5), or lower-alkoxycarbonyl,
R1, R3, R4, R5 and R6 independently from each other are hydrogen or lower-alkyl, or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof.
The present compounds of formula I and their salts and esters inhibit OSC and therefore also inhibit the biosynthesis of cholesterol, ergosterol and other sterols, and reduce the plasma cholesterol levels. They can therefore be used in the therapy and prophylaxis of hypercholesterolemia, hyperlipemia, arteriosclerosis and vascular diseases in general. Furthermore, they can be used in the therapy and/or prevention of mycoses, parasite infections, gallstones, cholestatic liver disorders, tumors and hyperproliferative disorders, e.g. hyperproliferative skin and vascular disorders. In addition, it has unexpectedly been found that the compounds of the present invention can also be of therapeutical use to improve glucose tolerance in order to treat and/or prevent related diseases such as diabetes. The compounds of the present invention further exhibit improved pharmacological properties compared to known compounds.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term xe2x80x9clowerxe2x80x9d is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term xe2x80x9clone pairxe2x80x9d refers to an unbound electron pair, in particular to the unbound electron pair of a nitrogen atom in e.g. an amine.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine, with chlorine, bromine and iodine being preferred.
The term xe2x80x9calkylxe2x80x9d, alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms. Alkyl groups can be substituted e.g. with halogen, CN, NO2 and/or aryl. Other, more preferred substituents are hydroxy, lower-alkoxy, aryl, NH2, N(lower-alkyl)2 and/or lower-alkoxy-carbonyl.
The term xe2x80x9clower-alkylxe2x80x9d, alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like. A lower-alkyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a monovalent carbocyclic radical of 3 to 10 carbon atom(s), preferably 3 to 6 carbon atoms. A cycloalykl group may also be bicyclic. A cycloalkyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d. Cycloalkyl in which one or xe2x80x94CH2xe2x80x94 group is replaced by O, S, NH or N(lower-alkyl) are referred to as xe2x80x9cheterocycloalkylxe2x80x9d.
The term xe2x80x9calkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is an alkyl. The term xe2x80x9clower alkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is a lower alkyl.
The term xe2x80x9calkenylxe2x80x9d, alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 20, preferably up to 16 carbon atoms. The term xe2x80x9clower-alkenylxe2x80x9d refers to a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propenyl. An alkenyl or lower-alkenyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkadienylxe2x80x9d, alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising 2 olefinic bonds and up to 20, preferably up to 16 carbon atoms. The term xe2x80x9clower-alkadienylxe2x80x9d refers to a straight-chain or branched hydrocarbon residue comprising 2 olefinic bonds and up to 7 carbon atoms. An alkadienyl or lower-alkadienyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkinylxe2x80x9d, alone or in combination with other groups, stands for a straight-chain or branched hydrocarbon residue comprising a tripple bond and up to 20, preferably up to 16 carbon atoms. The term xe2x80x9clower-alkinylxe2x80x9d refers to a straight-chain or branched hydrocarbon residue comprising a tripple bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propinyl. An alkinyl or lower-alkinyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkylenexe2x80x9d refers to a straight chain or branched divalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms. The term xe2x80x9clower-alkylenexe2x80x9d refers to a straight chair, or branched divalent saturated aliphatic hydrocarbon group of 1 to 7, preferably 2 to 4 carbon atoms. An alkylene or lower-alkylene group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkenylenexe2x80x9d refers to a straight chain or branched divalent hydrocarbon group comprising an olefinic bond and up to 20 carbon atoms, preferably up to 16 carbon atoms. The term xe2x80x9clower-alkenylenexe2x80x9d refers to a straight chain or branched divalent hydrocarbon group comprising an olefinic bond and up to 7, preferably up to 4 C-atoms. An alkenylene or lower-alkenylene group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9carylxe2x80x9d relates to the phenyl or naphthyl group which can optionally be mono- or multiply-substituted by lower-alkyl, lower-alkyl-di-oxo, halogen, hydroxy, cyano, CF3, NH2, N(lower-alkyl)2, aminocarbonyl, carboxy, nitro, lower-alkoxy, lower-alkylcarbonyl, lower-alkylcarbonyloxy, aryl, or aryloxy. Preferred substituents are lower-alkyl, fluorine, chlorine, bromine, lower-alkoxy, cyano, CF3, NO2, NH2, and/or N(lower-alkyl)2. More preferred substituents are chlorine and CF3.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic 5- or 6-membered ring which can comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, with furyl, thienyl and pyridyl being preferred. The term xe2x80x9cheteroarylxe2x80x9d further refers to bicyclic aromatic groups comprising two 5- or 6-membered rings, in which one or both rings can contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulphur such as e,g, indol or chinolin. A heteroaryl group may have a substitution pattern as described earlier in connection with the term xe2x80x9carylxe2x80x9d.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
The term xe2x80x9cpharmaceutically acceptable estersxe2x80x9d embraces esters of the compounds of formula (I), in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
The term xe2x80x9cprotecting groupxe2x80x9d refers to groups such as acyl, azoyl, alkoxycarbonyl, aryloxycarbonyl, or silyl. Examples are e.g. t-butyloxycarbonyl or benzyloxycarbonyl which can be used for the protection of amino groups or trimethylsilyl or dimethyl-tert.-butyl-silyl, which can be used for the protection of hydroxy groups.
In detail, the present invention relates to compounds of formula (I) 
wherein
U is O or a lone pair,
Y is C or N,
V is O, S, NR6, xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, if Y is C, or xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, if Y is N,
W is CO, COO, CONR1, CSO, CSNR1, SO2, or SO2NR1,
L is lower-alkylene, lower-alkenylene, or a single bond,
A1 is H, lower-alkyl, or lower-alkenyl,
A2 is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl, or lower-alkinyl, optionally substituted by R2,
A3, A4 are hydrogen or lower-alkyl, or
A1 and A2 or A1 and A3 are bonded to each other to form a ring and xe2x80x94A1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94A3xe2x80x94 are lower-alkylene or lower-alkenylene, optionally substituted by R2, in which one xe2x80x94CH2xe2x80x94 group of xe2x80x94A1xe2x80x94A2xe2x80x94 or xe2x80x94A1xe2x80x94A3xe2x80x94 can optionally be replaced by NR3, S, or O,
A5 is lower-alkyl,
X is hydrogen or one or more optional halogen substituents,
A6 is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, heterocycloalkyl-lower-alkyl, lower alkenyl, lower-alkadienyl, aryl, aryl-lower-alkyl, heteroaryl, or heteroaryl-lower-alkyl,
R2 is hydroxy, hydroxy-lower-alkyl, lower-alkoxy, N(R4,R5), or lower-alkoxycarbonyl,
R1, R3, R4, R5 and R6 independently from each other are hydrogen or lower-alkyl, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Preferred are compounds of formula (I) and/or pharmaceutically acceptable salts thereof. Another preferred embodiment relates to compounds of formula (I) wherein U is a lone pair. Other preferred compounds of formula (I) are those wherein U is O. Further, compounds of formula (I) in which Y represents C are preferred.
Compounds of formula (I) in which V is O, xe2x80x94Cxe2x89xa1Cxe2x80x94, or xe2x80x94CH2xe2x80x94 relate to another preferred embodiment of the present invention. Compounds of formula (I) in which V represents O are particularly preferred.
Of the compounds of the present invention, those in which W represents COO, SO2, or CSNR1 and R1 is hydrogen are preferred, as are those in which L is lower-alkylene or a single bond, or more preferrably L is xe2x80x94(CH2)2-4xe2x80x94.
Other preferred compounds of formula (I) are those in which A1 represents methyl, ethyl or 2-propenyl. Another group of preferred compounds of formula (I) are those in which A2 represents lower-alkyl, cycloalkyl, lower-alkenyl, or lower-alkinyl, optionally substituted with R2, wherein R2 is hydroxy, methoxy, or ethoxycarbonyl, with those compounds wherein A2 represents methyl, ethyl, 2-hydroxyethyl, or 2-propenyl being especially preferred.
Compounds of formula (I), wherein A1 and A2 are bonded to each other to form a ring and xe2x80x94A1xe2x80x94A2xe2x80x94 is lower-alkylene, or lower-alkenylene, optionally substituted by R2, in which one xe2x80x94CH2xe2x80x94 group or xe2x80x94A1xe2x80x94A2xe2x80x94 can optionally be replaced by NR3, S, or O, wherein R2 and R3 are as defined above are also preferred, with compounds wherein R2 is methyl, hydroxy, 2-hydroxyethyl, or N(CH3)2 and/or R3 is methyl being particularly preferred. In compounds wherein A1 and A2 are bonded to each other to form a ring, said ring is preferrably a 5-, 6- or 7-membered ring such as e.g. piperidinyl or pyrrolidinyl.
Further individually preferred embodiments of the present invention relate to compounds of formula (I) wherein A3 represents hydrogen and to compounds of formula (I) wherein A4 represents hydrogen. Compounds of formula (I) in which A5 is methyl or ethyl are also preferred, as are compounds of formula (I) in which X is hydrogen.
Compounds of formula (I), wherein A6 represents lower-alkyl, lower-alkenyl, phenyl or phenyl-lower-alkyl, wherein the phenyl group can optionally be substituted by one or more substituents selected from the group consisting of lower-alkyl, lower-alkoxy, fluorine, chlorine, bromine, CN, CF3, NO2, or N(R6,R7), wherein R6 and R7 independently from each other are hydrogen or lower-alkyl, are another preferred embodiment of the present invention, with those compounds wherein A6 is 4-trifluoromethyl-phenyl or 4-chloro-phenyl being particularly preferred.
Preferred compounds of general formula (I) are those selected from the group consisting of
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(2,4-difluoro-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(2,4-dimethoxy-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-fluoro-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-methoxy-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-p-tolyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-methoxy-2-methyl-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(2,4-dimethyl-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(3,4,5-trimethoxy-phenyl)-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(3,4-dimethyl-phenyl)-1-methyl-urea,
3-(4-Acetyl-phenyl)-1-{4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy],-phenyl}-3-(4-butyl-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(4-methylsulfanyl-phenyl)-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-isopropyl-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(3,4-dichloro-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-bromo-phenyl)-1-methyl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-naphthalen-2-yl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-naphthalen-1-yl-urea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-phenethyl-urea,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid ethyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid 9H-fluoren-9-ylmethyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid 2,2,2-trichloro-1,1-dimethyl-ethyl ester,
{4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid 4-nitro-phenyl esterxe2x80x9d
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid isobutyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid vinyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid benzyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid allyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid phenyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid butyl ester,
{4-(4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamoyloxy)-benzoic acid methyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid p-tolyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid 4-bromo-phenyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid 4-fluoro-phenyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid 4-chloro-phenyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid hexyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid 4-methoxy-phenyl ester,
5-Chloro-thiophene-2-sulfonic acid {4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4,N-dimethyl-benzenesulfonamide,
Naphthalene-2-sulfonic acid {4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amide,
Quinoline-8-sulfonic acid {4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-C-phenyl-methanesulfonamide,
3,5-Dimethyl-isoxazole-4-sulfonic acid {4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amide,
Naphthalene-1-sulfonic acid {4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amide,
N-{ 4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-methoxy-N-methyl-benzenesulfonamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-fluoro-N-methyl-benzenesulfonamide,
Thiophene-2-sulfonic acid {4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-2-fluoro-N-methyl-benzenesulfonamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-tert-butyl-N-methyl-benzenesulfonamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-butoxy-N-methyl-benzenesulfonamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-chloro-N-methyl-benzenesulfonamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-bromo-N-methyl-benzenesulfonamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-nicotinamide, 1H-Indole-2-carboxylic acid {4-[6-((allyl-methyl-amino)-hexyloxy]-phenyl}xe2x80x94methyl-namide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl-methyl-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-chloro-N-methbenzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-fluoro-N-methyl-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-bromo-N-methyl-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzamide,
Thiophene-3-carboxylic acid {4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amide,
5-Bromo-thiophene-2-carboxylic acid {4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-2-thiophen-3-yl-acetamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-2-(2,4-difluoro-phenyl)-N-methyl-acetamide,
5-Fluoro-1H-indole-2-carboxylic acid {4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-2-(4-fluoro-phenyl)-N-methyl-acetamide,
1H-Indole-5-carboxylic acid {4-[6-(allyl- methyl-amino)-hexyloxy]-phenyl}-methyl-amid,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-chloro-N-methyl-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-fluoro-3,N-dimethyl-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-4-nitro-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4,N-dimethyl-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-cyano-N-methyl-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3,N-dimethyl-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3,4-dimethoxy-N-methyl-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-methoxy-N-methyl-benzamide,
N-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-4-fluoro-N-methyl-3-nitro-benzamide,
4-Acetyl-N-{4-[6-(allyl-methamino)-hexyloxy]-phenyl}-N-methyl-benzamide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid 4-acetylamino-phenyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
Pyridine-2-carboxylic acid {4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amide,
N-[4-(6-Azepan-1-yl-hexyloxy)-phenyl]-4-bromo-N-methyl-benzenesulfonamide,
4-Bromo-N-(4-{6-[(2-methoxy-ethyl)-methyl-amino]-hexyloxy}-phenyl)-N-methyl-benzenesulfonamide,
4-Bromo-N-{4-[6-(ethyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Bromo-N-methyl-N-{4-[6-(2-methyl-piperidin-1-yl)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Bromo-N-(4-{6-[(2-hydroxy-ethyl)-methyl-amino]-hexyloxy}-phenyl)-N-methyl-benzenesulfonamide,
[(6-{4-[(4-Bromo-benzenesulfonyl)-methyl-amino]-phenoxy}-hexyl)-methyl-amino]-acetic acid ethyl ester,
4-Bromo-N-{4-[6-(butyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Bromo-N-[4-(6-diallylamino-hexyloxy)-phenyl]-N-methyl-benzenesulfonamide,
4-Bromo-N-methyl-N-[4-(6-pyrrolidin-1-yl-hexyloxy)-phenyl]-benzenesulfonamide,
4-Bromo-N-methyl-N-{4-[6-(methyl-prop-2-ynyl-amino)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Bromo-N-methyl-N-[4-(6-piperidin-1-yl-hexyloxy)-phenyl]-benzenesulfonamide,
4-Bromo-N-{4-[6-(ethyl-isopropyl-amino)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Bromo-N-methyl-N-[4-(6-morpholin-4-yl-hexyloxy)-phenyl]-benzenesulfonamide,
4-Bromo-N-{4-[6-(isopropyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Bromo-N-{4-[6-(3,6-dihydro-2H-pyridin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Bromo-N-(4-{6-[ethyl-(2-hydroxy-ethyl)-amino]-hexyloxy}-phenyl)-N-methyl-benzenesulfonamide,
4-Bromo-N-[4-(6-dimethylamino-hexyloxy)-phenyl]-N-methyl-benzenesulfonamide,
4-Bromo-N-methyl-N-{4-[6-(methyl-propyl-amino)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Bromo-N-{4-[6-(2,5-dihydro-pyrrol-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Bromo-N-[4-(6-diethylamino-hexyloxy)-phenyl]-N-methyl-benzenesulfonamide,
4-Bromo-N-methyl-N-[4-(6-thiomorpholin-4-yl-hexyloxy)-phenyl]-benzenesulfonamide,
4-Bromo-N-{4-[6-(butyl-ethyl-amino)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Bromo-N-{4-[6-(4-hydroxy-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Bromo-N-methyl-N-{4-[6-(4-methyl-piperazin-1-yl)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Bromo-N-{4-[6-(3-hydroxy-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Bromo-N-{4-[6-(3-dimethylamino-pyrrolidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Bromo-N-{4-[6-(4-hydroxymethyl-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
N-[4-(6-Azepan-1-yl-hexyloxy)-phenyl]-4-fluoro-N-methyl-benzenesulfonamide,
4-Fluoro-N-(4-{6-[(2-methoxy-ethyl)-methyl-amino]-hexyloxy}-phenyl)-N-methyl-benzenesulfonamide,
N-{4-[6-(Ethyl-methyl-amino)-hexyloxy]-phenyl}-4-fluoro-N-methyl-benzenesulfonamide,
4-Fluoro-N-methyl-N-{4-[6-(2-methyl-piperidin-1-yl)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Fluoro-N-(4-{6-[(2-hydroxy-ethyl)-methyl-amino]-hexyloxy}-phenyl)-N-methyl-benzenesulfonamide,
[(6-{4-[(4-Fluoro-benzenesulfonyl)-methyl-amino]-phenoxy}-hexyl)-methyl-amino]-acetic acid ethyl ester,
N-{4-[6-(Butyl-methyl-amino)-hexyloxy]-phenyl}-4-fluoro-N-methyl-benzenesulfonamide,
N-[4-(6-Diallylamino-hexyloxy)-phenyl]-4-fluoro-N-methyl-benzenesulfonamide,
4-Fluoro-N-methyl-N-[4-(6-pyrrolidin-1-yl-hexyloxy)-phenyl]-benzenesulfonamide,
4-Fluoro-N-methyl-N-{4-[6-(methyl-prop-2-ynyl-amino)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Fluoro-N-methyl-N-[4-(6-piperidin-1-yl-hexyloxy)-phenyl]-benzenesulfonamide,
N-{4-[6-(Ethyl-isopropyl-amino)-hexyloxy]-phenyl}-4-fluoro-N-methyl-benzenesulfonamide,
4-Fluoro-N-methyl-N-[4-(6-morpholin-4-yl-hexyloxy)-phenyl]-benzenesulfonamide,
4-Fluoro-N-{4-[6-(isopropyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
N-{4-[6-(3,6-Dihydro-2H-pyridin-1-yl)-hexyloxy]-phenyl}-4-fluoro-N-methyl-benzenesulfonamide,
N-(4-{6-[Ethyl-(2-hydroxy-ethyl)-amino]-hexyloxy}-phenyl)-4-fluoro-N-methyl-benzenesulfonamide,
N-[4-(6-Dimethylamino-hexyloxy)-phenyl]-4-fluoro-N-methyl-benzenesulfonamide,
4-Fluoro-N-methyl-N-{4-[6-(methyl-propyl-amino)-hexyloxy]-phenyl}-benzenesulfonamide,
N-{4-[6-(2,5-Dihydro-pyrrol-1-yl)-hexyloxy]-phenyl}-4-fluoro-N-methyl-benzenesulfonamide,
N-[4-(6-Diethylamino-hexyloxy)-phenyl]-4-fluoro-methyl-benzenesulfonamide,
4-Fluoro-N-methyl-N-[4-(6-thiomorpholin-4-yl-hexyloxy)-phenyl]-benzenesulfonamide,
N-{4-[6-(Butyl-ethyl-amino)-hexyloxy]-phenyl}-4-fluoro-N-methyl-benzenesulfonamide,
4-Fluoro-N-{4-[6-(4-hydroxy-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Fluoro-N-methyl-N-{4-[6-(4-methyl-piperazin-1-yl)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Fluoro-N-{4-[6-(3-hydroxy-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Fluoro-N-{4-[6-(4-hydroxymethyl-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
N-[4-(6-Azepan-1-yl-hexyloxy)-phenyl],-4-chloro-N-methyl-benzenesulfonamide,
4-Chloro-N-(4-{6-[(2-methoxy-ethyl)-methyl-amino]-hexyloxy}-phenyl)-N-methyl-benzenesulfonamide,
4-Chloro-N-{4-[6-(ethyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Chloro-N-methyl-N-{4-[6-(2-methyl-piperidin-1-yl)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Chloro-N-(4-{[6-(2-hydroxy-ethyl)-methyl-amino]-hexyloxy}-phenyl)-N-methyl-benzenesulfonamide,
[(6-{4-[(4-Chloro-benzenesulfonyl)-methyl-amino]-phenoxy}-hexyl)-methyl-amino]-acetic acid ethyl ester,
N-{4-[6-(Butyl-methyl-amino)-hexyloxy]-phenyl}-4-chloro-N-methyl-benzenesulfonamide,
4-Chloro-N-[4-(6-diallylamino-hexyloxy)-phenyl]-N-methyl-benzenesulfonamide,
4-Chloro-N-methyl-N-[4-(6-pyrrolidin-1-yl-hexyloxy)-phenyl]-benzenesulfonamide,
4-Chloro-N-methyl-N-{4-[6-(methyl-prop-2-ynyl-amino)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Chloro-N-methyl-N-[4-(6-piperidin-1-yl-hexyloxy)-phenyl]-benzenesulfonamide,
4-Chloro-N-{4-[6-(ethyl-isopropyl-amino)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Chloro-N-methyl-N-[4-(6-morpholin-4-yl-hexyloxy)-phenyl]-benzenesulfonamide,
4-Chloro-N-{4-[6-(isopropyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Chloro-N-{4-[6-(3,6-dihydro-2H-pyridin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide, 4-Chloro-N-(4-{6-[ethyl-(2-hydroxy-ethyl)-amino]-hexyloxy}-phenyl)-N-methyl-benzenesulfonamide,
4-Chloro-N-[4-(6-dimethylamino-hexyloxy)-phenyl]-N-methyl-benzenesulfonamide,
4-Chloro-N-methyl-N-{4-[6-(methyl-propyl-amino)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Chloro-N-{4-[6-(2,5-dihydro-pyrrol-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Chloro-N-[4-(6-diethylamino-hexyloxy)-phenyl]-N-methyl-benzenesulfonamide,
4-Chloro-N-methyl-N-[4-(6-thiomorpholin-4-yl-hexyloxy)-phenyl]-benzenesulfonamide,
N-{4-[6-(Butyl-ethyl-amino)-hexyloxy]-phenyl}-4-chloro-N-methyl-benzenesulfonamide,
4-Chloro-N-{4-[6-(4-hydroxy-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Chloro-N-methyl-N-{4-[6-(4-methyl-piperazin-1-yl)-hexyloxy]-phenyl}-benzenesulfonamide,
4-Chloro-N-{4-[6-(3-hydroxy-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Chloro-N-{4-[6-(3-dimethylamino-pyrrolidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
4-Chloro-N-{4-[6-(4-hydroxymethyl-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-benzenesulfonamide,
N-[4-(6-Azepan-1-yl-hexyloxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-(4-{6-[(2-Methoxy-ethyl)-methyl-amino]-hexyloxy}-phenyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(Ethyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-Methyl-N-{4-[6-(2-methyl-piperidin-1-yl)-hexyloxy]-phenyl}-4-trifluoromethyl-benzenesulfonamide,
N-(4-{6-[(2-Hydroxy-ethyl)-methyl-amino]-hexyloxy}-phenyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
[Methyl-(6-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-phenoxy}-hexyl)-amino]-acetic acid ethyl ester,
N-{4-[6-(Butyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(6-Diallylamino-hexyloxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-Methyl-N-[4-(6-pyrrolidin-1-yl-hexyloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide,
N-Methyl-N-{4-[6-(methyl-pr2-ynyl-amino)-hexyloxy]-phenyl}-4-trifluoromethyl-benzenesulfonamide,
N-Methyl-N-[4-(6-piperidin-1-yl-hexyloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(Ethyl-isopropyl-amino)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-Methyl-N-[4-(6-morpholin-4-yl-hexyloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(Isopropyl-methyl-amino)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(3,6-Dihydro-2H-pyridin-1-yl)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-(4-{6-[Ethyl-(2-hydroxy- ethyl)-amino]-hexyloxy}-phenyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(6-Dimethylamino-hexyloxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-Methyl-N-{4-[6-(methyl-propyl-amino)-hexyloxy]-phenyl}-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(2,5-Dihydro-pyrrol-1-yl)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(6-Diethylamino-hexyloxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-Methyl-N-[4-(6-thiomorpholin-4-yl-hexyloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(Butyl-ethyl-amino)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(4-Hydroxy-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-Methyl-N-{4-[6-(4-methyl-piperazin-1-yl)-hexyloxy]-phenyl}-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(3-Hydroxy-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(3-Dimethylamino-pyrrolidin-1-yl)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-{4-[6-(4-Hydroxymethyl-piperidin-1-yl)-hexyloxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-isopropyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-ethyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(5-Dimethylamino-pentyl)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-[5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-yl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
[4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester,
N-[4-(4-Diethylamino-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-carbamic acid 4-chloro-phenyl ester,
[4-(4-Dimethylamino-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester,
N-(4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-phenyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
[4-(4-Diethylamino-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester,
(4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-phenyl)-methyl-carbamic acid 4-chloro-phenyl ester,
4-[3-(Allyl-methyl-amino)-prop-1-ynyl]-phenyl}-methyl-carbamic acid 4-chloro-phenyl ester,
{4-[3-(Allyl-methyl-amino)-prop-1-ynyl]-phenyl}-methyl-carbamic acid 4-chloro-phenyl ester,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(2-bromo-4-fluoro-phenyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-bromo-2-methyl-phenyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(4-trifluoromethyl-phenyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-chloro-phenyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-methoxy-phenyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-cyano-phenyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(3 -methyl-butyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-sec-butyl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-cyclopropyl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(2,4-dichloro-benzyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(5-chloro-2-methoxy-phenyl)-1-methyl-thiourea,
1-{4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(2-methyl-5-nitro-phenyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(2,3-dihydro-benzo [1,4] dioxin-6-yl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(2-isopropyl-phenyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(3-phenyl-propyl)-thiourea,
3-(4-Acetyl-phenyl)-1-{4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-cyclohexylmethyl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(tetrahydro-furan-2-ylmethyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-fran-2-ylmetyl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-cyfopentyl-1-methyl-thiourea,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-bicyclo [2.2]hept-2-yl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-methyl3-(2,3,5,6-tetrafluoro-phenyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-[1-(4-fluoro-phenyl)-ethyl]-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-tert-butyl-phenyl)-e 1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(2,3,4-trimethoxy-benzyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(3-chloro-4-methyl-benzyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-pyridin-3-yl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-benzo[1,3]dioxol-5-ylmethyl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(4-methylsulfanyl-phenyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-cycloheptyl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(2-chloro-5-trifluoromethyl-phenyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-naphthalen-1-yl-thiourea,
1-14-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(2-cyclohex-1-enyl-ethyl)-1-methyl-thiourea,
(3-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-methyl-thioureido-acetic acid methyl ester,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-ethyl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-hexyl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-butyl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl-methyl-3-(2-methyl-butyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(2-methoxy-ethyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(3-methyl-butyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-phenyl-thiourea,
4-(3-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-methyl-thioureido-benzoic acid methyl ester,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-butyl-phenyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-pheny3-benzyl-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(4-methyl-benzyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-methoxy-benzyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-fluoro-benzyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-chloro-benzyl)-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(1-phenyl-ethyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-[2-(4-chloro-phenyl)-ethyl]-1-methyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-phenethyl-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-1-methyl-3-(2-p-tolyl-ethyl)-thiourea,
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-cyclohexyl-1-methyl-thiourea,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-thiocarbamic acid O-(4-chloro-phenyl) ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-thiocarbamic acid O-pentafluorophenyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-thiocarbamic acid O-(2,4,6-trichloro-phenyl)ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-thiocarbamic acid O-(4-fluoro-phenyl)ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid benzyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid phenyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid furan-2-ylmethyl amide,
({4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfonylamino)-acetic acid ethyl ester,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 2,2,2-trifluoro-ethyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid benzo[1,3]dioxol-5-ylmethyl amide,
4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid phenethyl amide,
4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid cycopropyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 2,2,2-trifluoro-ethyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 4-chloro-phenyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 4-bromo-phenyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid p-tolyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 4-trifluoromethyl-phenyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 4-cyano-phenyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 4-methoxy-phenyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 4-fluoro-phenyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 3,4-difluoro-phenyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 3-fluoro-phenyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 2,4-difluoro-phenyl amide,
{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-sulfamic acid 2,5-difluoro-phenyl amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid (4-chloro-phenyl)-amide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (4-chloro-phenyl)-amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid (4-fluoro-phenyl)-amide,
{4-[4-(Allyl-methyl-amino)xe2x80x94butoxy]-phenyl}-methyl-sulfamic acid (4-fluoro-phenyl)-amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid (4-bromo-phenyl)-amide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (4-bromo-phenyl)-amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid p-tolyl-amide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (p-tolyl)-amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid (3,4-difluoro-phenyl)-amide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (3,4-difluoro-phenyl)-amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid (4-trifluoromethyl-phenyl)-amide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (4-trifluoromethyl-phenyl)-amide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (3-fluoro-phenyl)-amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid (4-cyano-phenyl)-amide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (4-cyano-phenyl)-amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid (2,4-difluoro-phenyl)-amide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (2,4-difluoro-phenyl)-amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid (4-methoxy-phenyl)-amide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (4-methoxy-phenyl)-amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid (2,5-difluoro-phenyl)-amide,
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (2,5-difluoro-phenyl)-amide,
{4-[5-(Allyl-methyl-amino)-pentyloxy]-phenyl}-methyl-sulfamic acid (phenyl)-amide,
and {4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-sulfamic acid (phenyl)-amide, and
pharmaceutically acceptable salts thereof.
Particularly preferred compounds of general formula (I) are those selected from the group consisting of
{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-methyl-carbamic acid 4-chloro-phenyl ester,
N-{4-[4-(Allyl-methyl-amino)-butoxy]-phenyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(4-Diethylamino-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
[4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester,
[4-(4-Diethylamino-butoxy)-phenyl]-methyl- carbamic acid 4- chloro-phenyl ester,
(4-{ 4-[Ethyl-(2-hydroxy- ethyl)-amino]-butoxy}-phenyl)-methyl- carbamic acid 4-chloro-phenyl ester,
[4-(4-Dimethylamino-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester,
N-(4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-phenyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-ethyl-4-trifluoromethyl-benzenesulfonamide, and
1-{4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-3-(4-chloro-phenyl)-1-methyl-thiourea,
and pharmaceutically acceptable salts thereof.
Compounds of formula (I) can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers or as racemats. The invention embraces all of these forms.
It will be appreciated, that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
The present invention also relates to a process for the manufacture of compounds as described above, which process comprises reacting a compound of formula (II) 
wherein
X, Y, A5 have the significances given above,
Z is a group (A1,A2,)Nxe2x80x94C(A3,A4)xe2x80x94Lxe2x80x94Vxe2x80x94, halogenxe2x80x94CH2xe2x80x94Lxe2x80x94Vxe2x80x94, or halogen, wherein A1, A2, A3,A4, L and V have the significances given above,
or Z is Pxe2x80x94Vxe2x80x94 wherein V is O, S, or NR6, P is a protecting group and R6 is as defined above,
with ClSO2xe2x80x94A6, ClCOOxe2x80x94A6, ClCSOxe2x80x94A6, OCNxe2x80x94A6, SCNxe2x80x94A6, HOOCxe2x80x94A6, or ClSO2A6,
wherein A6 is as defined above.
In processes as described above wherein Z is halogen xe2x80x94CH2xe2x80x94Lxe2x80x94Vxe2x80x94, the term xe2x80x9chalogenxe2x80x9d preferrably refers to bromine. In processes as described above wherein Z is halogen, the term xe2x80x9chalogenxe2x80x9d preferrably refers to bromine or iodine.
The invention further relates to compounds of formula (I) as defined above, when manufactured according to a process as defined above.
As described above, the compounds of formula (I) of the present invention can be used for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections and gallstones, and/or treatment and/or prophylaxis of impaired glucose tolerance, diabetes, tumors and/or hyperproliferative disorders, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia. Hyperproliferative skin and vascular disorders particularly come into consideration as hyperproliferative disorders.
The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
Further, the invention relates to compounds as defined above for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia.
In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia, which method comprises administering a compound as defined above to a human being or animal.
The invention further relates to the use of compounds as defined above for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia.
In addition, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disorders, and/or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia. Such medicaments comprise a compound as defined above.
The compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given in the examples or by methods known in the art.
Compounds of formula (I), in which V represents O, NR6 or S and Y represents C can be prepared by the method outlined in scheme 1. In scheme 2, the preparation of compounds of formula (I), in which V represents xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94 and Y is C is outlined. Scheme 3 shows an overview of the preparation of compounds of formula (I) in which V represents xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94 and Y is N. 
In scheme 1, the synthesis is described for an 4-alkylaminobenzene-VH and 4-aminobenzene-VH, such as 4-alkylaminophenol, 4-aminophenol, 4-alkylamino-benzenethiol, 4-amino-benzenethiol or monoprotected 1,4-benzene-diamine, all possibly substituted by a group X. The 4-aminobenzene-VH are commercial available, the 4-alkylaminobenzene-VH are also commercially available or are synthesized by known procedures. 4-Alkyl-sidechain can alternatively be introduced in a later stage of the synthesis.
N-alkyl-p-anisidine is deprotected for example with 62% aqueous HBr in acetic acid at 110xc2x0 C. The resulting 4-alkylamino-phenol 1 as an example is then N-BOC-protected (reaction step a) in THF/acetonitril with pyridine (if the aminophenol is a salt) and di-tert-butyl dicarbonate at 70xc2x0 C. Alkylation of the (4-Hydroxy-phenyl)-alkyl-carbamic acid tert-butyl ester in acetone with K2CO3 and a suitable dihaloalkane, dihaloalkene, or a N-protected dihaloalkylaminoalkane (halogene is here represented by bromine, but can be also Cl or I. It is also possible to use mesylates or tosylates instead of halogenides) at reflux yields halogenide 3 (reaction step b). This compound is then converted (reaction step c) to the amine 4 in DMA at RT with an excess of the corresponding amine. Boc deprotection (reaction step d) in CH2Cl2 at xe2x88x9220xc2x0 C. with TFA, following by warming up to room temperature yields the alkyl-aniline 5. This intermediate compound is then converted to the compounds of the present invention 6 by one of the following reactions (step e):
Sulfonylation of compounds 5 is done in dioxane with Huinigsbase and a sulfonyl chloride over night at RT to give the sulfonamide 6. N-alkylation (in case A5xe2x95x90H) under Mitsunobu-conditions in THF with DEAD and the corresponding alcohol results in the final product 6 as a free amine.
Compounds 5 may be reacted with A6OCOCl/Huenigsbase in dioxane or A6OH/Cl3COCl/quinoline (formation of the chloroformate) may be reacted with compound 5 and Huenigsbase.
Compounds 5 may be reacted with A6OCSCl in dioxane.
Compounds 5 may be reacted with isocyanate in dioxane at room temperature.
Compounds 5 may be reacted with isothiocyanate in dioxane at room temperature.
Compounds 5 may be reacted with A6COOH/EDCI/DMAP (with anhydride formation, and subsequent addition of the starting amine at xe2x88x9210xc2x0 C. to room temperature) or as alternative with A6COOH/EDCI/DMAP or A6COOH/Huenigsbase/EDCI/HOBT in DMF, dioxane or CH2Cl2 at room temperature.
Compounds 5 may be reacted with sulfamoyl chlorides in dioxane in the presence of an excess of triethylamine to give sulfamide 6. The sulfamoyl chlorides are synthesized from A6NH2 and chiorosulfonic acid in CH2Cl2 at 0xc2x0 C. to room temperature followed by reaction with PCl5 in toluene at 75xc2x0 C. Alternatively, the sulfamoyl chlorides can be synthesized in acetonitrile with A6NH2 and sulfuryl chloride at 0xc2x0 C. to 65xc2x0 C.
Alternatively, the group A1A2NC(A3A4)Lxe2x80x94OH or the mesylate/halogenide of them can be synthesized by known methods and attached to compound 2 (Mitsunobu or alkylating conditions), to give directly amine 6 (reaction step f).
The amines 6 can optionally be converted to a salt or to the N-oxide 7 (reaction of compounds 6 with a mixture of hydrogen peroxid urea adduct and phthalic anhydride in CH2Cl2 at RT, reaction step g).
Another strategy outlined in scheme 1 is the introduction of the desired group xe2x80x94Wxe2x80x94A6 in compound 1. The 4-alkylaminophenol salt (e.g. hemisulfate) or another suitable compound as described above is persilylated (reflux in hexamethyldisilazane and evaporated) and reacted with a suitable sulfonyl chloride or chloroformate or is transformed in analogy to reaction step e as described above. Aqueous work-up (deprotection of the V-Silylprotection) yields compound 2.Alkylation of 2 with for example dihaloalkane in DMF with NaH as base yields halogenide 8 (reaction step b). Amination of the halogenide 8 as described above yields the final compound 6, which can optionally be transformed to salts or to the N-oxide 7.
A third possibility which is described in Scheme 1 is the deprotection of Boc-protected compound 3 (in CH2Cl2 at 0xc2x0 C. to RT with TFA during 20 min) which yields compound 9. With this compound, introduction of the Wxe2x80x94A6 group (which yields compound 8 in analogy to reaction step e as described above) followed by amination to the final compound 6 (reaction step c) as described above is also possible.
In scheme 2, the preparation of compounds of formula (I), in which V represents xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94 and Y is C is outlined starting from 4-Iodoaniline I as an example, which is BOC-protected with di-tert-butyl dicarbonate in THF for 30 h at 80xc2x0 C. and N-alkylated with A5-halogenide in THF at xe2x88x9218xc2x0 C. to RT with 55% NaH as base to yield compound 2 (reaction step a). Sonogashira-coupling (reaction step b) of the iodo-aniline derivative 2 and a suitable alkinol in piperidine with Pd(PPh3)4/CuI at 45xc2x0 C. to 80xc2x0 C. in analogy to a literature procedure [Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4), 649-672.]yields alcohol 3. Mesylation with methanesulfonylchloride/pyridine/DMAP (reaction step c) and subsequent amination (reaction step d) of the resulting mesylate 4 with a suitable amine in DMA at RT yields the amine 5. Boc-deprotection of 5 (reaction step e) in CH2Cl2 at a temperature between 0xc2x0 C. and RT with TFA during 20 min yields te aniline derivative 6. This intermediate compound is then converted to the compounds of the present invention 7 by introduction of the desired Wxe2x80x94A6 group (reaction step f) in analogy to the methods described above in context with scheme 1.
Optionally the alkine side chain can be hydrogenated in MeOH/dioxane/AcOH with Pd/C10% and hydrogene at 1 atm (reaction step g) to yield the corresponding saturated compound 7 in which V is xe2x80x94CH2xe2x80x94.
Alternatively compound 2 can be BOC-deprotected and the desired Wxe2x80x94A6 group can be introduced as described above (reaction steps e, f) to yield compound 9. The group A1A2NC(A3A4)L-acethylene can then be synthesized by known methods (see for example Imada, Yasushi; Yuasa, Mari; Nakamura, Ishin; Murahashi, Shun-Ichi. Copper(I)-Catalyzed Amination of Propargyl Esters. Selective Synthesis of Propargylamines, 1-Alken-3-ylamines, and (Z)-Allylamines. J. Org. Chem. (1994), 59(9), 2282-4) and attached to compound 9 (Sonogashira-coupling), to yield the compounds of the present invention 7 (reaction step b).
The compounds 7 can optionally be converted to a salt or to the N-oxide 8 (reaction of compounds 7 with a mixture of hydrogen peoxid urea adduct and phthalic anhydride in CH2Cl2 at RT, reaction step g).
Scheme 3 shows an overview of the preparation of compounds of formula (I) in which V represents xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94 and Y is N. As an example, BOC-protection of 2-amino-5-bromopyrimdine 1 with di-tert-butyl dicarbonate in THF/CH3CN with pyridine/DMAP at a temperature between RT and 80xc2x0 C. yields the di-BOC-pyrimidine 2 (reaction step a). Sonogashira-coupling of compound 2 with a suitable alkinol in DMF with Et3N, CuI PdCl2(dppf).CH2Cl2 at 80xc2x0 C. in analogy to a literature procedure [The synthesis followed a procedure of Arco Y. Jeng; Design and Synthesis of Potent, Selective Inhibitors of Endothelin-Converting Enzyme, Journal of Medicinal Chemistry; 1998; 41(9); 1513-1523.] yields alcohol 3 (reaction step b). Mesylation with methanesulfonylchloride/pyridine/DMAP (reaction step c) and subsequent amination (reaction step d) of the resulting mesylate 4 with a suitable amine in DMA at RT yields the amine 5. Compound 6 is obtained after Boc-deprotection in CH2Cl2 at 0xc2x0 C. to RT with TFA during 20 min (reaction step e). Sulfonylation of compound 6 with a suitable sulfonyl chloride in pyridine at 70xc2x0 C. overnight (reaction step f) yields compound 7 which is N-alkylated under Mitsunobu-conditions with triphenylphosphine/DEAD/alkanol in THF at 0xc2x0 C. to RT (reaction step g) to yield the compounds of the present invention 8.
Alternatively compounds 10 with suitable Wxe2x80x94A6 and A5 groups can be synthesized in analogy to the methods as described above (reaction steps f,g). Other residues A1A2NC(A3A4)L-acethylene can be synthesized by known methods (see for example Imada, Yasushi; Yuasa, Mari; Nakamura, Ishin; Murahashi, Shun-Ichi. Copper(I)-Catalyzed Amination of Propargyl Esters. Selective Synthesis of Propargylamines, 1-Alken-3-ylamines, and (Z)-Allylamines. J. Org. Chem. (1994), 59(9), 2282-4) and attached to compounds 10 (Sonogashira-coupling), to yield the compounds 8 (reaction step b) in analogy to the methods described above.
The compounds 8 can optionally be converted to a salt or to the N-oxide 9 (reaction step h) by the methods described above.
The following tests were carried out in order to determine the activity of the compounds of formula I and their salts.
Liver microsomes from a healthy volunteer were prepared in sodium phosphate buffer (pH 7.4). The OSC activity was measured in the same buffer, which also contained 1 mM EDTA and 1 mM dithiothreitol. The microsomes were diluted to 0.8 mg/ml protein in cold phosphate buffer. Dry [14C]R,S-monooxidosqualene (MOS, 12.8 mCi/mmol) was diluted to 20 nCi/xcexcl with ethanol and mixed with phosphate bufferxe2x80x941% BSA (bovine serum albumin). A stock solution of 1 mM test substance in DMSO was diluted to the desired concentration with phosphate bufferxe2x80x941% BSA. 40 xcexcl of microsomes were mixed with 20 xcexcl of the solution of the test substance and the reaction was subsequently started with 20 xcexcl of the [14C]R,S-MOS solution. The final conditions were: 0.4 mg/ml of microsomal proteins and 30 xcexcl of [14C]R,S-MOS in phosphate buffer, pH 7.4, containing 0.5% albumin, DMSO  less than 0.1% and ethanol  less than 2%, in a total volume of 80 xcexcl.
After 1 hour at 37xc2x0 C. the reaction was stopped by the addition of 0.6 ml of 10% KOH-methanol, 0.7 ml of water and 0.1 ml of hexane:ether (1:1, v/v) which contained 25 xcexcg of non-radioactive MOS and 25 xcexcg of lanosterol as carriers. After shaking, 1 ml of hexane:ether (1:1, v/v) was added to each test tube, these were again shaken and then centrifuged. The upper phase was transferred into a glass test tube, the lower phase was again extracted with hexane:ether and combined with the first extract. The entire extract was evaporated to dryness with nitrogen, the residue was suspended in 50 xcexcl of hexane:ether and applied to a silica gel plate. Chromatographic separation was effected in hexane:ether (1:1, v/v) as the eluent. The Rf values for the MOS substrate and the lanosterol product were 0.91 and, respectively, 0.54. After drying, radioactive MOS and lanosterol were observed on the silica gel plate. The ratio of MOS to lanosterol was determined from the radioactive bands in order to determine the yield of the reaction and OSC inhibition.
The test was carried out on the one hand with a constant test substance concentration of 100 nM and the percentage OSC inhibition against controls was calculated. The more preferred compounds of the present invention exhibit inhibitions larger than 50%. In addition, the test was carried out with different test substance concentrations and subsequently the IC50 value was calculated, i.e. the concentration required to reduce the conversion of MOS into lanosterol to 50% of the control value. The preferred compounds of the present invention exhibit IC50 values of 1 nM to 10 xcexcM, preferrably of 1-100 nM.
The compounds of formula I and their pharmaceutically acceptable acid addition salts and esters can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and their pharmaceutically acceptable acid addition salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to about 1000 mg, especially about 50 mg to about 500 mg, comes into consideration for the prevention and control of topical and systemic infections by pathogenic fungi. For cholesterol lowering and treatment of impaired glucose tolerance and diabetes the daily dosage conveniently amounts to between 1 and 1000 mg, preferably 10 to 100 mg, for adult patients. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.
The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 10-100 mg, of a compound of formula I.
The following Examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.